Polymorphism in Erlotinib Hydrochloride: New Insights into Relative Stability, Thermal Behavior, and Structural Differences of Forms A and B

Erlotinib hydrochloride (EtbHCl), whose polymorphism is still ill-characterized, is an essential component of the current armamentarium for the treatment of pancreatic and lung cancers. It recently became a textbook example of the importance of crystal polymorphism for drug development and patent litigation. In this work, a quantitative evaluation of the relative thermodynamic stability of the two most important EtbHCl polymorphs (forms A and B) was performed. Based on calorimetric and solubility studies, the standard molar Gibbs energy, enthalpy, and entropy of the B(cr) → A(cr) transition at 298 K were obtained as Δ trs G m ° (B → A) = 2.4 ± 1.0 kJ mol −1, Δ trs H m ° (B → A) = 6.1 ± 1.1 kJ mol −1, and T Δ trs S m ° (B → A) = 3.7 ± 1.5 kJ mol –1, respectively. These results unequivocally indicate that form B is more stable than form A at, or close to, ambient temperature and that the larger stability of form B is enthalpically determined (hence of lattice energy origin). The solubility measurements (gastric fluid at pH 1.2, 298 ± 1 K) evidenced a 2.6 times larger solubility of form A relative to form B. This suggests that a significant bioavailability enhancement may be potentially obtained if form A rather than form B is used in EtbHCl formulations. Differential scanning calorimetry and hot-stage microscopy experiments indicated that the two forms are monotropically related and exhibit considerably different thermal behaviors: on heating form B from 298 K, only fusion was observed; in contrast, the fusion of form A is followed by the formation of plate-like crystals that subsequently transform into a needle-like phase that subsequently melts. None of these two high-temperature phases should correspond to form B, given that melting occurs at a significantly lower temperature than the fusion of form B. Finally, insights into the structural differences between the two forms were provided by combining information from the previously reported crystal structure of form B and from FT-IR and Raman microspectroscopy experiments carried out on both forms. The overall results suggest that (i) the ethynylphenyl and quinazoline ring systems of the EtbHCl molecule are likely to be more coplanar and adopt a different conformation in form A ( anti ) than in form B ( syn ); (ii) a nonclassical C≡C–H···O hydrogen bond interaction, which is evident in the crystal structure of form B, is not present or is substantially weaker in form A.